Lubiprostone in Chronic Kidney Disease: Insights into Mitochondrial 5 Function and Polyamines from a Randomized Phase 2 Clinical Trial

Chronic kidney disease (CKD) is a life-threatening envents and constipation is a progressive risk factor. We assessed the changes in uremic toxins, renal function, and safety of a selective chloride channel activator, lubiprostone in CKD patients. A total of 150 CKD patients (stage IIIb-IV) were enrolled in a phase II, randomized, multicenter, double-blind, placebo-controlled study across nine centers in Japan. Patients were randomized in a 2:2:3 to placebo, 8 microgram, or 16 microgram treatment for 24 weeks. Patients with eGFR of 36 to 45 and 25 to 35 mL/min/1.73 m2 were classified as having moderate and severe renal dysfunction, respectively. The primary endpoint was the change in indoxyl sulfate levels. Secondary endpoints, including other uremic toxins, changes in renal function (blood urea nitrogen, creatinine (Cr), cystatin C, eGFR, urinary protein, and the slope of the reciprocal of Cr), and defecation frequency were analyzed. Lubiprostone did not change uremic toxin levels but improved eGFRCr in the 16 microgram group and maintained eGFRCr and slopes of eGFRCr and 1/Cr. Both 8 microgram and 16 microgram doses were effective in moderate group. Mild-to-moderate adverse gastrointestinal events were reported in the placebo and 16 microgram groups. Multi-omics analyses revealed that lubiprostone modulated the gut microbial agmatine pathway and increased circulating spermidine levels, resulting in improved renal mitochondrial function. Lubiprostone is a novel and safe therapeutic agent that mitigates the decline in renal function in CKD patients.